This invention relates to novel organic compounds which are useful as pharmaceutical agents. The novel compounds of this invention modulate the activity of enzymes which control the processes of glycolysis and gluconeogenesis, two processes which help to regulate blood glucose levels in mammals. As such, the compounds of the present invention are useful for treating hyperglycemia and/or diabetes in warm-blooded animals. This invention also relates to methods for treating hyperglycemia and/or diabetes in mammals in need of such treatment, to pharmaceutical compositions for the utilization of these novel compounds in the treatment of hyperglycemia and/or diabetes and to processes for the chemical syntheses of these compounds.
The disease diabetes mellitus, commonly referred to as diabetes, is characterized by metabolic defects in the production and disposal of glucose. The result of these defects is the inability to maintain appropriate blood glucose (or blood sugar) levels. Treatments of diabetes have commonly employed the administration of exogenous insulin, the oral administration of drugs, or the use of dietary therapy. Initially, it was believed that the hyperglycemia observed in diabetics was simply the result of a deficiency in the supply of insulin, the principal hormone which controls glucose metabolism. As a result, research focused on the source of insulin production, the beta cells of the pancreas, and pharmaceutical agents which stimulated these cells to release insulin were developed.
Although it is true that a deficiency in insulin production can produce hyperglycemia, it has now been recognized that a variety of defects in metabolic processes can play a major role in the control of blood glucose levels. Metabolic processes which are important in this regard include glycolysis (the metabolic degradation of glucose to lactic acid), gluconeogenesis (the metabolic process by which endogenous synthesis of glucose from lactic acid occurs), glycogenolysis (the metabolic process by which glucose is released from stored glycogen), and insulin-stimulated glucose uptake (the metabolic process by which peripheral tissues acquire glucose as an energy source). Defects in any or all of these metabolic processes have significant effects on the maintenance of appropriate blood glucose levels.
In Type I diabetes, also called juvenile-onset or insulin-dependent diabetes, a deficiency in insulin production is the major cause of hyperglycemia. However, the majority of diabetics suffer from a form of the disease referred to as Type II, also called maturity-onset or noninsulin-dependent diabetes. In most Type II diabetics, basal insulin levels are normal or even elevated; in spite of this, transient or continuous elevations in blood glucose levels occur. In such disease states, the metabolic processes mentioned above, which normally function to provide exquisite control over blood glucose levels, are operating in an aberrant manner. Thus, a pharmaceutical agent capable of regulating these processes would be useful in restoring normal metabolic control of blood sugar levels.
Two of the above-described metabolic processes which are vitally important to glucose homeostasis are glycolysis and gluconeogenesis. In the process called glycolysis, glucose is converted in a series of enzymatically catalyzed transformations to lactic acid. In the process called gluconeogenesis, glucose is synthesized from lactic acid in another series of enzymatically catalyzed transformations. It is well known that proper regulation of these two metabolic processes is essential for the maintenance of appropriate blood glucose levels.
In recent years, research has resulted in the discovery of a natural product, beta-D-fructose-2,6-bisphosphate (Pilkis et al., J. Biol. Chem 256, 3171-3174 (1981)), which has now been demonstrated to be an important regulator of both glycolysis and gluconeogenesis Beta-D-fructose-2,6-bisphosphate exerts its regulatory action on these metabolic processes by specifically modulating the activity of a key enzyme involved in each of these processes. First, beta-D-fructose-2,6-bisphosphate promotes glycolysis by stimulating the enzyme 6-phosphofructo-1-kinase, which catalyzes the conversion of fructose-6-phosphate to fructose-1,6-bisphosphate. Second, beta-D-fructose-2,6-bisphosphate attenuates gluconeogenesis by inhibiting the enzyme fructose-1,6-bisphosphatase, which catalyzes the conversion of fructose-1,6-bisphosphate to fructose-6-phosphate. Either or both of these regulatory actions serve to reduce glucose levels, the former by promoting the metabolic degradation of glucose and the latter by attenuating the endogenous synthesis of glucose. Thus, the net result of the regulatory action of beta-D-fructose-2,6-bisphosphate is a lowering of glucose levels, the exact result desired in the treatment of hyperglycemic and/or diabetic states.
It has now been found that the novel organic compounds of the present invention exert regulatory actions on the key enzymes of the glycolytic and gluconeogenic processes in exactly the same manner as the natural product, beta-D-fructose-2,6-bisphosphate. The novel compounds are more resistant to enzymatic or hydrolytic degradation than the natural product, which has a labile acetal phosphate group. The novel compounds are stimulators of the enzyme 6-phosphofructo-1-kinase and inhibitors of the enzyme fructose-1,6-bis-phosphatase; the net result of these actions being the lowering of glucose levels. As such, they are useful for the treatment of hyperglycemic and/or diabetic states in mammals.